Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer
Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer
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DOI：
10.1158/0008-5472.can-05-2693
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Johnston, PG
中科院分区：
文献类型：
--
作者：
Boyer, J;Allen, WL;Johnston, PG
DNA 微阵列分析用于分析 HCT116 结直肠癌细胞的转录谱，这些细胞经过 5-氟尿嘧啶 (5-FU) 或奥沙利铂处理，并选择对这些药物的耐药性。生物信息学分析确定了耐药细胞中组成性失调的基因组，并在亲本细胞急性暴露于药物后短暂改变。我们认为这些基因可能代表对 5-FU 和奥沙利铂敏感的分子特征。使用实时逆转录 PCR (RT-PCR)，我们的微阵列数据显示出稳健性，代表性基因子集 >= 82%（奥沙利铂）和 > 85%（5-FU）的表达趋势具有很强的整体一致性。此外，对于 (R-2 >= 0.73) 和奥沙利铂基因集 (R-2 >= 0.63)，观察到基因表达平均倍数变化的微阵列和实时 RT-PCR 测量之间存在很强的相关性。对微阵列研究中鉴定的三个基因[前列腺衍生因子（PDF）、钙结合蛋白和亚精胺/精胺N-1-乙酰转移酶（SSAT）]的功能分析揭示了它们作为细胞毒性药物反应的新型调节剂的重要性。这些数据显示了这种基于微阵列的新型方法在识别可能是重要标记的基因方面的能力。对治疗的反应和/或治疗干预的目标。
DNA microarray analysis was used to analyze the transcriptional profile of HCT116 colorectal cancer cells that were treated with 5-fluorouracil (5-FU) or oxaliplatin and selected for resistance to these agents. Bioinformatic analyses identified sets of genes that were constitutively dysregulated in drug-resistant cells and transiently altered following acute exposure of parental cells to drug. We propose that these genes may represent molecular signatures of sensitivity to 5-FU and oxaliplatin. Using real-time reverse transcription-PCR (RT-PCR), the robustness of our microarray data was shown with a strong overall concordance of expression trends for >= 82% (oxaliplatin) and > 85% (5-FU) of a representative subset of genes. Furthermore, strong correlations between the microarray and real-time RT-PCR measurements of average fold changes in gene expression were observed for both the (R-2 >= 0.73) and oxaliplatin gene sets (R-2 >= 0.63). Functional analysis of three genes identified in the microarray study [prostate-derived factor (PDF), calretinin, and spermidine/spermine N-1-acetyl transferase (SSAT)] revealed their importance as novel regulators of cytotoxic drug response. These data show the power of this novel microarray-based approach to identify genes which may be important markers. of response to treatment and/or targets for therapeutic intervention.